1. Field of the Invention
The present invention relates to a method of using Transforming Growth Factor beta 1 (TGF.beta.1) as a chemoprotective agent for cycle active drugs such as cyclophosphimide and melphalan, and more specifically, to a method for protecting bone marrow using TGF.beta.1.
2. Description of Related Art
Transforming growth factor .beta. (TGF.beta.1) (Roberts A. B. et al, Proc. Natl. Acad. Sci. USA, 82:119, (1985)) has been shown to both stimulate and inhibit (Sporn, M. B. et al, J. Cell Biol. 105:1039 (1987); Robey, P. G. et al, J. Cell Biol. 105:457 (1987); Centrella, M. et al, J. Biol. Chem. 262:2869 (1987); Roberts, A. B. et al, Proc. Natl. Acad. Sci. USA 82:119 (1985); Arteaga, C. L. et al, Cancer Res. 48:3898 (1988)) the proliferation of several cell types, as well as suppress a variety of cytokine-induced immunological responses (Kehrl, J. et al, J. Immunol. 137:3855 (1986); Kehrl, J. H. et al, J. Exp. Med. 163:1037 (1986); Espevik, T. et al, J. Immunol. 140:2312 (1988)). Previous studies from the laboratory of the present inventors have demonstrated that TGF.beta.1 selectively inhibits the proliferation and differentiation of early hematopoietic progenitor cells in vitro (Keller, J. R. et al, J. Exp. Med. 169:737 (1988); Sing, G. K. et al, Blood 72:1504 (1988)). The studies reported herein are performed to determine whether similar effects of TGF.beta.1 on bone marrow cells could be achieved in vivo. Since the pharmacodynamics of exogenously administered TGF.beta.1 have been reported to be unfavorable due to binding to serum components such as .alpha.2-macroglobulin (O'Connor, M. D. et al, J. Biol. Chem. 262:14090 (1987)) and first-pass hepatic extraction (Coffey, R. J. et al, J. Clin. Invest. 80:750 (1987)) the present inventors have developed a surgical technique to administer TGF.beta.1 locoregionally via injection into the femoral artery. This approach allows the determination of the in vivo effects following injection of microgram amounts of TGF.beta.1 on proliferation and maturation of early hematopoietic progenitor cells. The results of these studies show that relatively small amounts of TGF.beta.1 inhibit baseline and IL-3 (interleukin 3) driven proliferation of these progenitor cells in a time-and dose-dependent manner.